Rev. Bras. Anestesiol. vol.63 número1 en v63n1a15

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Rev Bras Anestesiol. 2013;63(1):163-166

Ofﬁ cial Publication of the Brazilian Society of Anesthesiology www.sba.com.br/rba/index.asp

REVISTA

BRASILEIRA DE

ANESTESIOLOGIA

Precipitation in Gallipoli: Sugammadex / Amiodarone &

Sugammadex / Dobutamine & Sugammadex / Protamine

LETTER TO THE EDITOR

Dear Editor,

Sugammadex is a modifi ed gamma cyclodextrin 1-3_{. Cyclodextrins}

are water soluble cyclic oligosaccharides with a lipophilic core. Sugammadex has quickly found a place in clinical use for selective antagonism of neuromuscular blockade with

ro-curonium 1-3_{. Sugammadex quickly encapsulates steroidal}

neu-romuscular blockers, increasing the amount of encapsulated steroidal neuromuscular blockers in plasma and separating the

blockers from the nicotinic acetylcholine receptors 1-3_.

Apart from its use with steroidal neuromuscular block-ers, it is known that sugammadex interacts with over 40 lipophilic, steroidal and non-steroidal drugs. These drugs include: propofol, thiopental, fentanyl, remifentanil, van-comycin, gentamicin, salbutamol, aminophylline, atropine, digoxin, ephedrine, phentolamine, verapamil, cortisone and

hydrocortisone 4_.

Previous research shows that, apart from steroidal muscle relaxants, sugammadex forms precipitates with

protamine 5_.

There is no clinical data on whether sugammadex forms precipitates with other drugs, commonly used in clinical prac-tice. The hypothesis of this study is to investigate whether the chemical and physical properties of sugammadex would contribute to a precipitation reaction with drugs commonly used in clinical practice.

With this aim, simply 0.1 mL containing 100 mg.mL-1

sug-ammadex was mixed on a glass slide with the same volume of a drug and the presence or absence of precipitation was determined under the microscope. The drugs investigated are all commonly used in clinical anesthesia practice. They

include: adrenalin (1 mg.mL-1_{), atropine (1 mg.mL}-1_),

amio-darone (50 mg.mL-1_{), aminophylline (24 mg.mL}-1_{), ornidazole}

(500 mg.3 mL-1_{), bupivacaine (5 mg.mL}-1_{), cefazolin sodium}

(250 mg.mL-1_{), dexmedetomine (100 µg.mL}-1_{), dobutamine}

(12.5 mg.mL-1_{), dopamine (8 mg.mL}-1_{), ephedrine (0.05 g.mL}-1_),

esmolol (10 mg.mL-1_{), esomeprazole (40 mg.mL}-1_{), etomidate}

(2 mg.mL-1_{), fentanyl (50 µg.mL}-1_{), fl umazenil (0.1 mg.mL}-1_),

furosemide (10 mg.mL-1_{), gentamicin (40 mg.mL}-1_{), glyceryl}

trinitrate (5 mg.mL-1_{), heparin (1,000 IU.mL}-1_),

hydrocor-tisone (250 mg.mL-1_{), crystallized insulin (100 IU.mL}-1_),

Calcium (Calcium Gluconate Monohydrate 225 mg.10 mL-1

+ Calcium levulinate dihitrate 572 mg.10 mL-1_{), ketamine}

(50 mg.mL-1_{), levobupivacaine (7.5 mg.mL}-1_{), magnesium}

sulphate (1.2 mEq.mL-1_{), metamizol sodium (0.5 g.mL}-1_),

methylergobasin maleate (0.2 mg.mL-1_{), metoclopramide}

(5 mg.mL-1_{), metoprolol (1 mg.mL}-1_{), morphine (0.01 g.mL}-1_),

midazolam (5 mg.mL-1_{), n-acetylcysteine (100 mg.mL}-1_),

naloxone (0.4 mg.mL-1_{), neostigmine (0.5 mg.mL}-1_),

nitroprus-side (12 mg.mL-1_{), noradrenaline (1 mg.mL}-1_{), oxytocin (5 IU.mL}-1_),

paracetamol (10 mg.mL-1_{), thiopental sodium (25 mg.mL}-1_),

pethidine (50 mg.mL-1_{), pheniramine (22.75 mg.mL}-1_),

phenytoin (50 mg.mL-1_{), piracetam (1 g.5 mL}-1_{), prednisolone}

(25 mg), prilocaine (20 mg.mL-1_{), propafenone (3.5 mg.mL}-1_),

pro tamine hydrochloride (1,000 IU.mL-1_{), potassium (1 mEq.mL}-1_),

remifentanil (5 mg.mL-1_{), cefuroxime axetil (125 mg.mL}-1_),

sulbactam-ampicillin (200 mg.mL-1_{), succinylcholine}

(20 mg.mL-1_{), tenoxicam (10 mg.mL}-1_{), theophylline (24 mg.}

mL-1_{), tramadol (50 mg.mL}-1_{), and vitamin K (10 mg.mL}-1_).

A scale of 0-4 was used to evaluate the test, with 0 being no precipitation and 4+ being strong precipitation.

Within seconds, sugammadex (100 mg.mL-1_{) scored 4+}

pre-cipitation with amidarone (50 mg.mL-1_{), dobutamine (12.5 mg.}

mL-1_{) and protamine hydrochloride (1,000 IU.mL}-1_).

There are reports on the incompatibility and precipitation

of anesthetic drugs 5-7_{. Thiopental, with basic pH, reacts with}

acidic muscle relaxants such as suxamethonium,

mivacu-rium, vecuronium and rocuronium, causing precipitation 8_.

Similarly, thiopental causes precipitation with local

anesthet-ics due to pH differences 9_{. Previous experimental studies}

have shown that thiopental reacting with various drugs may form thiopental acid crystals due to precipitation, which

may cause pulmonary embolism 10_{. Sugammadex has a pH of}

7.5 and the precipitation reaction with protamine may be

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164 V. Hanci et al.

Our study shows that sugammadex reacts with amiodar-one, dobutamine and protamine under in-vitro conditions, causing precipitation. We emphasize that sugammadex should not be given intravenously simultaneously with these drugs. Future studies will characterize their precipitation reaction, which seems to be only the tip of the iceberg. In addition, future studies should be focused on investigating sugammadex compatibility with other drugs by using Gas Chromatography/Mass Spectrometry device. We believe the effects of this precipitation on the drugs’ effi cacy and circulation warrants further research.

*Volkan Hancı, MD, Assoc. Prof. **Hasan Ali Kiraz, MD, Assist. Prof.

**Dilek Ömür, MD, Assist. Prof. **Serpil Ekin, MD, Assistant Doctor **Berna Uyan, MD, Assistant Doctor ***Bulent Serhan Yurtlu, MD, Assist. Prof.

Departments of Anaesthesiology and Reanimation, * Dokuz Eylul University (formerly Canakkale Onsekiz Mart University)

** Canakkale Onsekiz Mart University *** Dokuz Eylul University (formerly Bulent Ecevit

University), Turkey

References

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general anesthesia: focus on sugammadex. Drug Des Devel Ther, 2009;3:119-129.

3. Rex C, Bergner UA, Pühringer FK – Sugammadex: a selective relaxant-binding agent providing rapid reversal. Curr Opin Anaesthesiol, 2010;23:461-465.

4. Zhang M-Q – Drug-specifi c cyclodextrins: the future of rapid neuromuscular block reversal? Drugs Future. 2003;28:347-354. 5. Alston TA – Precipitation of sugammadex by protamine. J Clin

Anesth, 2011;23:593.

6. Smith RP, Jones M – Precipitation in Manchester: ketorolac/ cyclizine. Anaesthesia, 2001;56:494-495.

7. Ackland G – Physical incompatibility between atracurium and intravenous diclofenac. Anaesthesia, 2001;56:294.

8. Khan S, Stannard N, Greijn J – Precipitation of thiopental with muscle relaxants: a potential hazard. JRSM Short Rep, 2011;2:58.

9. Waters JH, Rizzo VL, Ramanathan S – A re-evaluation of the ability of thiopental to identify cerebrospinal fl uid in epidural catheter aspirate. J Clin Anesth, 1995;7:224-227.